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First published on October 27, 2004; DOI: 10.1124/mol.104.003996

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Received for publication June 23, 2004.
Revised October 18, 2004.
Accepted for publication October 26, 2004.

Picrotoxin Accelerates Relaxation of GABAC Receptors

Haohua Qian 1*, Yi Pan 2, Yujie Zhu 3, Parham Khalili 3

1 Univ. of Illinois at Chicago 2 Department of Biological Sciences, University of Illinois at Chicago 3 University of Illinois at Chicago

* Address correspondence to: E-mail: hqian{at}uic.edu

Abstract

Picrotoxin is a plant alkaloid that is often used to block the activity of neuronal GABA and glycine receptors. However, the mechanism by which picrotoxin inhibits these receptors is still in debate. In this study, we investigated the picrotoxin inhibition on perch {rho} subunits expressed heterologously in Xenopus oocytes, and on native GABAC receptors of perch bipolar cells. Both competative and non-competative mechanisms were observed for picrotoxin inhibition of the GABAC receptor. In oocytes expressing the {rho}1A subunit, terminating simultaneously the co-application of GABA and picrotoxin induced a large rebound of membrane current. In addition, picrotoxin significantly accelerated the kinetics of GABA responses, particularly in the relaxation (offset) phase of GABA currents. Both current rebound and the large acceleration of GABA relaxation were unique to picrotoxin inhibition, and were not observed with the competitive antagonist TPMPA or the allosteric modulator zinc. The change in kinetics induced by picrotoxin was also observed on receptors formed by other GABA {rho} subunits, as well as on the GABAC receptors of retinal bipolar cells. Based on these observations, we proposed a model in which picrotoxin binds to the GABAC receptor in both channel open and closed states. Overall, this model provides a remarkably good approximation of the experimental findings we observed for picrotoxin inhibition of GABAC receptors. These results support an allosteric mechanism of picrotoxin inhibition of ligand-gated chloride channels.


Key words: GABAA, GABAC, Glycine, Molecular dynamics


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